Atypical cyclins: the extended family portrait

Abstract

Regulation of cell division is orchestrated by cyclins, which bind and activate their catalytic workmates, the cyclin-dependent kinases (CDKs). Cyclins have been traditionally defined by an oscillating (cyclic) pattern of expression and by the presence of a characteristic "cyclin box" that determines binding to the CDKs. Noteworthy, the Human Genome Sequence Project unveiled the existence of several other proteins containing the "cyclin box" domain. These potential "cyclins" have been named new, orphan or atypical, creating a conundrum in cyclins nomenclature. Moreover, although many years have passed after their discovery, the scarcity of information regarding these possible members of the family has hampered the establishment of criteria for systematization. Here, we discuss the criteria that define cyclins and we propose a classification and nomenclature update based on structural features, interactors, and phylogenetic information. The application of these criteria allows to systematically define, for the first time, the subfamily of atypical cyclins and enables the use of a common nomenclature for this extended family.

Keywords: Canonical; Cell cycle; Cyclin family; Phosphorylation; Transcriptional.

Fig. 1

Conservation of critical residues for CDK binding. Multiple sequence alignment of the cyclins region critical for CDK binding [30] was conducted using Jalview software set to Clustal Omega. The resulting alignment (manually refined) was grouped into canonical and transcriptional cyclins (a) as they are considered bona fide cyclins, or potential cyclins (b) and exported to ExPASy BoxShade to highlight conservation (black boxes = conserved). c Cyclin F (CCNF)/F-box only protein 1 (FBXO1) sequence alignment. Logos for cyclin consensus sequences were identified using WebLogo [112]. Red dots indicate the Lys–Glu pair conserved among cyclins; gray dots indicate the Glu–Glu pair that is only present in canonical and transcriptional cyclins. Aminoacid sequences were retrieved from UniProt; positions of the N-terminal cyclin boxes used for the alignment were retrieved from Pfam, a database of curated protein families defined by multiple sequence alignments and hidden Markov model profiles [113]

Fig. 2

CDK–cyclin interactions. Cyclins were grouped into canonical, transcriptional, and atypical cyclins, whereas CDKs were grouped into cell cycle, transcriptional, and atypical CDKs as described by Malumbres, 2014 [4]. The table shows the reported CDK–cyclin interactions. For atypical cyclins, a systematic search in the STRING database was conducted [114]. Only the interactions supported by experimental data were selected and further revised for confirmation. a reviewed in [3]; b [115]; c [54]; d [66]; e [84]; f [70]; g [116]

Fig. 3

Human cyclin proteins. Sequence-based phylogenetic tree of human cyclins. The tree was generated by bootstrap analysis of the N-terminal cyclin box amino acid sequence using Clustal Omega. All the proteins containing either a Pfam domain PF00134 or PF08613 were included in the analysis. The length of the proteins, as well as the length of the domains, are on scale